Introduction To PK Rutgers iJOBS Seminar AAbrahamijobs.rutgers.edu/other/Introduction To PK...

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Introduction to Pharmacokinetics (PK)Anson K. Abraham, Ph.D.Associate Principal Scientist, PPDM-‐QP2Merck & Co. Inc., West Point, PA5-‐June-‐2017

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Outline

• Definition & Relevance of Pharmacokinetics & Pharmacodynamics (PK/PD)

• Small v/s Large Molecules

• Fundamental Concepts of PK

• Q&A

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What is Pharmacokinetics?

• Pharmacokinetics (PK)– What the body does to the drug

Parent DrugMetabolite

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Distribution


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Distribution

Elimination


ADME

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PK Profiles Based on Route of Administration & Multiple Dosing

AUC: Area Under the Curve (measure of drug exposure)

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What is Pharmacodynamics?

• Pharmacodynamics (PD)– What the drug does to the body

Parent DrugActive Metabolite

PD Effect of Proton Pump Inhibition

Rev Esp Enferm Dig. 2012 Jul;;104(7):367-78

http://annals.org/data/Journals/AIM/19857/6FF5.jpeg

PD Effect of Anti-Viral Drugs

Transporter Occupancy of Duloxetine

JPET, April 2012, 341 (1) 137-145

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Has an Increased Understanding of PK/PD Helped?

Attrition of drug candidates

Nature Reviews Drug Discovery 2, 192-204 (March 2003) Nature Reviews Drug Discovery 14, 475–486 (2015)

Better understanding of PK/PD principles seems to have shifted the drug attrition profile

n = 198

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Why is PK/PD Important? A Recent Example

• Selecting the right Drug and Dose in the right Population

Right Drug Right Dose & Regimen Right Population

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Recent Example from PD-1 Inhibitors in Oncology

http://onlinelibrary.wiley.com/doi/10.1002/psp4.12140/full#psp412140-fig-0003Journal for ImmunoTherapy of Cancer, 2017, 5:43

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Small vs Large Molecule

http://www.amgenbiosimilars.com/the-‐basics/the-‐power-‐of-‐biologics/

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Small vs Large Molecule• For matters related to PK/PD, molecular size and structure matters!!!

Small Molecule:• Oral dosing route is generally preferred

• Half-life in body is typically in hours

• Additional PK considerations• Absorption characteristics from gut after oral dosing

• First-pass metabolism (liver)• Potential for drug-drug interactions

• Renal elimination• No immunogenicity concerns• Can access intra-cellular targets

Large Molecule:• IV/SC/IM dosing routes e.g. palivizumab (IM)

• Half-life in body is typically in days

• Additional PK considerations• Absorption characteristics from skin after SC dosing

• No first-pass metabolism (liver)• Minimal potential for drug-drug interactions

• Non-renal elimination mechanisms

• Immunogenicity concerns i.e. body can generate an immune response

• Primarily binds to extracellular targets

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ADME -‐ Absorption

• Absorption is dependent on various physicochemical and physiological factors. The key parameters are – Solubility in the GIT– Permeability across the GI membrane

Parent Drug

AAPS J. 2012 Jun; 14(2): 244–251

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ADME -‐ Absorption

• Passive Diffusion v/s Active Transport– Passive diffusion occurs based on a concentration gradient between

intestinal lumen and portal vein concentrations– Active transport of drug molecules is mediated through transporter

proteins with potential for capacity limitation (e.g. glucose & β-‐lactams)

Concentration

Initial Rate of

Absorption

Passive Diffusion

Active Transport

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fg fhfa

Extent of Absorption (Small Molecules Oral Dosing)• Extent of absorption i.e. Bioavailability (F)

– Fraction absorbed from lumen (fa): Fraction of drug in the GI lumen that enters gut tissues

– Fraction absorbed from gut wall (fg): Fraction of drug in gut wall that enters the portal vein i.e. fraction escaping gut metabolism

– Hepatic fraction absorbed (fh): Fraction of drug in the portal vein that enters systemic circulation

– Hepatic Extraction Ratio (ER): Fraction of the drug that is extracted by the liver

𝐹 = 𝑓$ % 𝑓& % 𝑓' 𝑓' = (1 − 𝐸𝑅)

Nature Reviews Drug Discovery 2, 192-204 (March 2003)

F is relevant for SC or IM injections as well

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Rate of Absorption (Small Molecules)

• Rate of absorption i.e. how fast the drug enters systemic circulation– Determines the time (tmax) to maximum concentration (Cmax)– For orally absorbed drugs, rate of absorption is generally described by

a first-‐order rate constant, ka. Units of ka is 1/time– Inverse relationship of ka with tmax

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Question 1

• If the fraction of drug absorbed at each stage i.e. fa, fg, and fh is 50%, then what the bioavailability (F)?

– A: 2500.0%– B: 25.5%– C: 12.5%

𝐹 = 𝑓$ % 𝑓& % 𝑓'

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Question 1 Solution

• If the fraction of drug absorbed at each stage i.e. fa, fg, and fh is 50%, then what the bioavailability (F)?

– C: 12.5%𝐹 = 𝑓$ % 𝑓& % 𝑓'

Explanation: F = 0.5 x 0.5 x 0.5 = 0.125 x 100 = 12.5%

• Drugs like vancomycin and gentamycin are polar with MWT >400 g/mole. These drugs have low F due to low fa

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ADME -‐ Distribution

• Volume of distribution (V) of a drug is an apparent volume that correlates amount and concentration of drug in the body

• Typical physiological volumes include:

𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 =𝐴𝑚𝑜𝑢𝑛𝑡𝑉𝑜𝑙𝑢𝑚𝑒

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Why is “V” an Apparent Volume of Distribution?

• Reported volumes greatly exceed physiological volumes

• Apparent “V” is determined by factors such as polarity, lipophilicity, and ionization state (pKa)

Rowland, M., Tozer, T. N., & Rowland, M. (2011). Clinical pharmacokinetics and pharmacodynamics: Concepts and applications. Philadelphia: Wolters Kluwer Health/Lippincott William & Wilkins.

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Volume of Distribution (V or Vd)

• Volume of distribution is useful to calculate a loading dose

500mg

500 mL 1 mg/mL

Time

Concentration (C)

I.V. Bolus

Ctime=0 = Dose / V


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Volume of Distribution is Apparent

500mg

water water500 mL

ConcWater = 1 mg/mL;;

Thus V = 500 mL

𝑉𝑜𝑙𝑢𝑚𝑒 =𝐴𝑚𝑜𝑢𝑛𝑡

𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛

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500mg

water water

water

octanol500mg 500 mL

500 mL

500 mL


Thus V = 500 mL

water

octanol1:1

ConcWater = 0.5 mg/mL;;

Thus V = 1000 mL

𝑉𝑜𝑙𝑢𝑚𝑒 =𝐴𝑚𝑜𝑢𝑛𝑡

𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛

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• Partitioning contributes to an increase in apparent volume of distribution– Lipophilic drugs that distribute extensively into tissues e.g. diazepam

(V = 168 L)– Vmay approach physiological volumes e.g. monoclonal antibodies at

high doses

500mg

water water

water

octanol500mg 500 mL

500 mL

500 mL


Thus V = 500 mL

water

octanol

1 (water):9 (octanol)

ConcWater = 0.1 mg/mL;;

Thus V = 5000 mL

1Gibaldi, M. 1984 "Biopharmaceutics and Clinical Pharmacokinetics", 3rd ed., Lea & Febiger, Chapter 12, page 214

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PK Models – One or More Compartments

• Poly-‐exponential PK indicates distribution phenomenon (non-‐specific or target-‐related)

• A poly-‐exponential PK curve will required two or more compartments for adequate characterization of data

Time

Log Concentration (C)

Mono-exponential

Time

Log Concentration (C)

Poly-exponential

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Question 2

• Which drug has a larger volume of distribution?

Drug A

Drug B

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Question 2: Solution

• Which drug has a larger volume of distribution?– Answer: Drug B

Drug A

Drug B

For any drug, a large apparent V is not necessarily a disadvantage. The absolute value of V is indicative of where the drug is distributed as well as physicochemical properties of the drug


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ADME – Metabolism & Elimination

•Hepatic & Gut Metabolism– CYP, UGT, etc… enzymes

• Renal Elimination• Various terms referring to Elimination– Clearance i.e. CL (Units: volume/time)

§ For an organ, the maximal clearance is equal to blow flow to that organ» Liver blood flow = 1.5 L/min» Kidney blood flow = 1.2 L/min» Glomerular Filtration Rate i.e. GFR = 0.1 L/min

– Elimination Rate Constant i.e. kel (Units: 1/time)

– Elimination half-‐life i.e. thalf (Units: time)

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Clearance (CL)

• Drug CL is the volume that is cleared of a drug per unit of time

. . . .. .

.......

Volume

Concentration. . . .

. ..

...

t = 0

...

e.g: t = 1 sec

CL = 3 drops/sec

. . . .. . .

..

. ...

CL = 6 drops/sec

e.g: t = 1 sec

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. . . .. .

.......

Volume

Concentration. . . .

. ..

...

t = 0

...

e.g: t = 1 sec

CL = 3 drops/sec

. . . .. . .

..

. ...

CL = 6 drops/sec

e.g: t = 1 sec

..

..

....

. ... ...

Clearance at Steady-‐State(CL)• At steady-‐state, Rate In = Rate Out

• For IV infusions, the dosing rate can be calculated using CL and required steady state concentration

. . .

𝐼𝑛𝑓𝑢𝑠𝑖𝑜𝑛?$@A = 𝐶𝐿 % 𝐶𝑜𝑛𝑐CC

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Total Clearance

Total CL is representative of the sum of all clearance mechanisms and organs

CL = CLgut + CLliver + CLkidney

Time

Concentration (C)

Concentration

Rate GFR

Concentration

Rate Secretion by Active Transport

Concentration

Rate Metabolism by CYPs

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Impact of Clearance on PK

• CL is an important determinant of drug exposure (AUC)

𝐶𝐿 = 𝐷𝑜𝑠𝑒. 𝐹𝐴𝑈𝐶0−inf

, 𝑤ℎ𝑒𝑟𝑒 𝐹 = 1 𝑓𝑜𝑟 𝐼𝑉

Low CL

High CL

Minimal Efficacious Concentration

Maximum Safe Concentration

Ideal CL

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Metabolism

• Primarily impacts small molecules• Four common type of reactions include:

– Oxidation: Majorly mediated through cytochrome P450 (CYP) enzymes– Hydrolysis: Aspirin to salicylic acid and acetic acid– Reduction– Conjugation: Phase 2 reactions such as glucuronidation

• Metabolites are typically more polar and water soluble. Hence, lower reabsorption

• In some cases, metabolites may also be active– Prodrug: Codeine to morphine

• Characterizing metabolic profile of drugs is important to predict drug-‐drug interactions

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Question 3a

• Two drugs (A & B) are co-‐administered simultaneously. Drug A is known to induce the CYP3A4 enzyme. Drug B is primarily metabolized by CYP3A4 to an inactive metabolite. What is the impact on the PK (exposure) for both drugs compared to when these drugs are administered alone?A. AUC of Drug B is lowerB. AUC of both drugs A & B is lowerC. No impact on AUCD. AUC of Drug B is higher

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Question 3a: Solution

• Two drugs (A & B) are co-‐administered simultaneously. Drug A is known to induce the CYP3A4 enzyme. Drug B is primarily metabolized by CYP3A4 to an inactive metabolite. What is the impact on the PK (exposure) for both drugs compared to when these drugs are administered alone?A. AUC of Drug B is lower (efficacy may be compromised)B. AUC of both drugs A & B is lowerC. No impact on AUCD. AUC of Drug B is higher

Drug-drug interactions (DDI) are a major concern for drugs that are eliminated via the metabolic pathway. Enzyme induction may result in sub-therapeutic doses of drug.

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Question 3b

• Two drugs (A & B) are co-‐administered simultaneously. Drug A is known to inhibit the CYP3A4 enzyme. Drug B is primarily metabolized by CYP3A4 to an inactive metabolite. What is the impact on the PK (exposure) for both drugs compared to when these drugs are administered alone?A. AUC of Drug B is lowerB. AUC of both drugs A & B is lowerC. No impact on AUCD. AUC of Drug B is higher

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Question 3b: Solution

• Two drugs (A & B) are co-‐administered simultaneously. Drug A is known to inhibit the CYP3A4 enzyme. Drug B is primarily metabolized by CYP3A4 to an inactive metabolite. What is the impact on the PK (exposure) for both drugs compared to when these drugs are administered alone?A. AUC of Drug B is lower B. AUC of both drugs A & B is lowerC. No impact on AUCD. AUC of Drug B is higher (potential safety concern)

Drug-drug interactions (DDI) are a major concern for drugs that are eliminated via the metabolic pathway. This is especially true for drugs with a narrow therapeutic index.

An ideal drug candidate would have multiple elimination pathways, such that inhibiting any one pathway does not significantly impact exposures.

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Source: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination, Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e

Citation: Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e; 2011 Available at: http://accesspharmacy.mhmedical.com/content.aspx?bookid=1613&sectionid=102157226 Accessed: June 02, 2017

Copyright © 2017 McGraw-Hill Education. All rights reserved

The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action. Possibledistribution and binding of metabolites in relation to their potential actions at receptors are not depicted.

PK in a Nutshell – Use Free Drug Concentrations

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PK Analysis -‐ NCA

• Non-‐Compartmental Analysis– Slope (k)– Height (Cmax)– Area Under the Curve (AUC)

1

10

100

0 10 20 30 40 50

Plasma Concentration

Time

C(tn)

Cmax

AUC0-inf = AUC(0-tn) + C(tn)’/k

AUC (0-tn)

tn

slope = - k

AUC(tn-inf)Ideally <25% extrapolated area



𝐹 =𝐴𝑈𝐶𝑝𝑜𝐷𝑜𝑠𝑒KL

%𝐷𝑜𝑠𝑒𝑖𝑣𝐴𝑈𝐶NO

t1/2 = 0.693/kElimination half-life

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PK Analysis – Compartmental Evaluation

ka kelDose Comp.1

One compartment body model with first order absorption (e.g. Oral dose)

𝐶K =𝐷𝑜𝑠𝑒 % 𝐹 % 𝑘$𝑉 % (𝑘$ − 𝑘AQ)

(𝑒RSTU%@ − 𝑒RSV%@)

Goal: Estimate model parameters using non-linear regression

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Final Questions

• Assume same IV dose for drugs A & B• Q1: Which drug has higher CL?

1. A 2. B3. A = B

AUC = 10 AUC = 10

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Final Questions

• Assume same IV dose for drugs A & B• Q1: Which drug has higher CL?

1. A 2. B3. A = B

AUC = 10 AUC = 10



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Final Questions

• Assume same dose for drugs A & B • CL = 1.5 L/min• Q2: Which compound has greater tissue distribution?

1. A 2. B

AUC = 10 AUC = 10

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Final Questions

• Assume same dose for drugs A & B • CL = 1.5 L/min• Q2: Which compound has greater tissue distribution?

1. A 2. B

AUC = 10 AUC = 10

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Final Questions

• Assume same dose for drugs A & B • CL = 1.5 L/min• Q3: Is glomerular filtration the sole mechanism of elimination?

1. Yes2. No

AUC = 10 AUC = 10

Hint: GFR is ~0.1 L/min

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Final Questions

• Assume same dose for drugs A & B • CL = 1.5 L/min• Q3: Is glomerular filtration the sole mechanism of elimination?

1. Yes2. No

AUC = 10 AUC = 10

Hepatic metabolism could be a major and sole elimination pathway as well.

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Model-‐Based Drug Development: A Rational Approach to Efficiently Accelerate Drug Development

Clinical Pharmacology & TherapeuticsVolume 93, Issue 6, pages 502-514, 14 MAR 2013 DOI: 10.1038/clpt.2013.54http://onlinelibrary.wiley.com/doi/10.1038/clpt.2013.54/full#cptclpt201354-fig-0001

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Examples Where Model-‐Based Analysis Has Helped Speed Up Drug Development

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Clinical Pharmacology & TherapeuticsVolume 93, Issue 6, pages 502-‐514, 14 MAR 2013

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Label – Sections Informed by PKPD Information

FULL PRESCRIBING INFORMATION: CONTENTS* WARNING – LIFE-THREATENING HEMATOLOGICAL ADVERSE REACTIONS 1 INDICATIONS AND USAGE

1.1 Thrombotic Stroke 1.2 Coronary Stenting

2 DOSAGE AND ADMINISTRATION 2.1 Thrombotic Stroke 2.2 Coronary Stenting 2.3 Renally Impaired Patients

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

5.1 Hematological Adverse Reactions 5.2 Monitoring for Hematological Adverse Reactions 5.3 Anticoagulant Drugs 5.4 Bleeding Precautions 5.5 Monitoring: Liver Function Tests

6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience

7 DRUG INTERACTIONS 7.1 Anticoagulant Drugs 7.2 Phenytoin 7.3 Antipyrine and Other Drugs Metabolized Hepatically 7.4 Aspirin and Other Non-Steroidal Anti-Inflammatory Drugs 7.5 Cimetidine 7.6 Theophylline 7.7 Propranolol 7.8 Antacids 7.9 Digoxin 7.10 Phenobarbital 7.11 Other Concomitant Drug Therapy 7.12 Food Interaction

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment

10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Thrombotic Stroke 14.2 Coronary Stenting 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

17.1 Importance of Monitoring 17.2 Bleeding 17.3 Hematological Adverse Reactions 17.4 FDA-Approved Patient Labeling

*Sections or subsections omitted from the full prescribing information are not listed.

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PK Optimization in Drug Development

Nature Reviews Drug Discovery 2, 192-‐204 (March 2003)

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Thank You!!!

Introduction To PK Rutgers iJOBS Seminar AAbrahamijobs.rutgers.edu/other/Introduction To PK...

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